It has been estimated that up to 45% of deaths in the United States can be attributed to fibroproliferative diseases, which can affect many tissues and organ systems. Fibrosis affects nearly all tissues and organ systems. Diseases in which fibrosis is a major cause of morbidity and mortality include the interstitial lung diseases, liver cirrhosis, liver fibrosis resulting from chronic hepatitis B or C infection, kidney disease, heart disease, and systemic sclerosis. Fibroproliferative disorders also include systemic and local scleroderma, keloids and hypertrophic scars, atherosclerosis, restenosis, and eye diseases including macular degeneration and retinal and vitreal retinopathy. Additional fibrotic disorders include excessive scarring resulting from surgery, chemotherapeutic drug-induced fibrosis, radiation-induced fibrosis, and injuries and burns. Fibrotic tissue remodeling can also influence cancer metastasis and accelerate chronic graft rejection in transplant recipients [28].
Fibrosis is central to the pathogenesis of many chronic lung disorders, including asthma, pneumoconioses, and many infections. The quintessential fibrotic lung diseases, however, are the fibrotic interstitial lung diseases, usual interstitial pneumonia (UIP) and fibrotic variant of non-specific interstitial pneumonia (NSIP). These illnesses are of unknown cause and are characterized by progressive lung fibrosis, typically culminating in respiratory failure and premature death. No treatment has been clearly effective in altering the clinical course of these diseases, and there is an urgent need for better understanding of their pathogenesis [1].
Dysregulated tissue remodeling is fundamental to the development of fibrotic lung diseases: UIP and fibrotic NSIP share the histologic features of relatively mild leukocyte infiltration but prominent accumulation of extracellular matrix in the form of dense or loose fibrosis [2]. They are distinguished by the variegated pattern of pathology in UIP, in which normal areas are juxtaposed with areas with leukocyte infiltration and other areas with advanced fibrosis, whereas fibrotic NSIP is homogenous in its distribution [3-5]. In addition, the pathological lesion of fibroblastic foci, which consist of concentrated numbers of fibroblasts and myofibroblasts associated with focal injury and generation of new collagen, is more prominent in UIP than fibrotic NSIP [6-8].
The source of lung fibroblasts and myofibroblasts is a critical question in the pathogenesis of fibrotic diseases such as lung fibrotic diseases. While these cells were classically thought to be derived exclusively from resident lung fibroblasts, recent studies indicate that they can differentiate from pulmonary epithelial cells [9] and from a circulating precursor cell, the fibrocyte [10]. Fibrocytes are bone marrow-derived cells with monocytic morphology, that express surface markers of leukocytes and haematopoietic stem cells but also collagen-I; and are capable of differentiating into diverse cell types [11-13]. It has been previously shown that, in a mouse model of bleomycin-induced pulmonary fibrosis, both mouse and human fibrocytes can traffic to the lung and contribute to collagen deposition and accumulation of α-smooth muscle actin (αSMA)-expressing cells in the lung [10]. Furthermore, the recruitment of these cells was mediated via the interaction of the chemokine ligand, CXCL12, in the lung and the receptor, CXCR4, on fibrocytes.
There is a long felt need in the art for methods to diagnose and treat fibrotic disease. The present invention satisfies these needs.